Targeting the sinusoidal-to-capillarized transition to normalize vessels in breast cancer liver metastasis

Liver metastases exhibit marked resistance to anti-VEGF anti-angiogenic therapies, yet the underlying mechanisms remain poorly understood. By combining single-cell RNA sequencing of human breast cancer liver metastases with a liver sinusoidal endothelial cell (LSEC) lineage-tracing mouse model, we show that liver metastasis-associated vessels originate from Lyve1+ sinusoidal endothelial cells but undergo a sinusoidal-to-capillarized transition as they grow into the metastatic nodule, characterized by enhanced inflammatory signaling, loss of sinusoidal markers, and acquisition of capillarized markers. We functionally perturbed each of these abnormalities individually. Unexpectedly, ectopic Lyve1 overexpression paradoxically enhanced hyaluronan and other extracellular matrix deposition in the tumor microenvironment, suggesting a compensatory mechanism. Similarly, targeting TNF signaling, a hallmark inflammatory pathway in liver metastasis, dampened the inflammatory state of metastasis-associated vessels but promoted metastatic outgrowth, indicating that TNF blockade is not a viable strategy for metastasis treatment. Strikingly, inhibition of the capillary tip cell marker Esm1 improved vessel perfusion and enhanced chemotherapeutic drug delivery, two defining features of vascular normalization. Pan-cancer analysis further revealed that Esm1 expression is restricted to tip cells and correlates with poor patient prognosis, positioning Esm1 as a candidate target for promoting vascular normalization. Collectively, our findings reveal the vascular plasticity of liver metastasis and, although not all abnormal features are actionable, we propose targeting Esm1 to inhibit sprouting angiogenesis and to normalize dysfunctional liver metastasis vessels, offering a promising therapeutic avenue for liver malignancies.